1. Field of the Invention
The present invention relates to a novel process for the preparation of enantiomerically pure nicotine analogs containing alkyl substituents on the pyridine ring at the 4, 5, and/or 6 positions. The invention also relates to intermediate compounds useful for the preparation of such nicotine analogs which analogs are useful as insecticides.
2. Description of the Prior Art
Nicotine has been used as an insecticide for many years. Yamamoto has studied a number of nicotinoids (both natural and synthetic) with regard to their insecticidal activity [Agr. Biol. Chem., 26, 709 (1962); Id., 27, 445 (1963); Id., 27, 450 (1963), Id., 27, 684 (1963); Id., 32, 568 (1968); Id., 32, 747 (1968); Id., 32, 1341 (1968)]. Several of the analogs studied possessed significant toxicity towards aphids, house flies, and cockroaches. Individual enantiomers of nicotinoids have been shown to display wide differences in insecticidal activity [Richardson, C., Craig, L., and Hansberry, R., J. Econ. Entomol., 29, 850 (1936); Hansberry, R., and Norton, L., Id., 33, 734 (1940)]. For example, d-nicotine was found to be five times less effective against aphids then when natural l-nicotine. Further differences in insectidal activity between individual enantiomers and their racemic mixtures were demonstrated: the racemic mixture, d, l-nicotine, was half as potent against aphids as l-nicotine and the racemic mixture, d, l-nornicotine, was less potent against aphids than either of its enantiomeric components although the individual d- and l-nornicotine enantiomers possessed comparable toxicity against aphids. Clearly, the optical activity of a given nicotinoid is important to its biological properties and methods for the production of nicotinoids having specific optical activity are of considerable interest.
McKennis has prepared (S)-cotinine, a nicotine analogue and metabolite from (S)-nicotine [Bowman, E. R., and McKennis, H. Jr., Biochem. Prep., 10, 36 (1963)]. Sanders prepared a mixture of (2'S)-cis-and-trans-5'-cyanonicotine from (S)-cotinine using the method of McKennis for the preparation of the (S)-cotinine [Sanders, E. B., DeBardeleben, J. F., and Osdene, T. S., J. Org. Chem., 40, 2848 (1975)]. Note that both McKennis and Sanders altered only the pyrrolidine ring of the nicotine skeleton.
Compare Haglid, F., Acta. Chem. Scand., 21, 329 (1967) which discloses nicotine analogs containing alkyl substituents on the pyridine ring. Haglid synthesized a mixture of 6-methylnicotine and 4-methylnicotine by the addition of methyllithium to (S)-(-)-nicotine. Although both products possessed optical activity [Id., at p. 333, Table 5], they appeared to have undergone partial racemization since the unreacted nicotine recovered had undergone racemization to a degree of 67%.
All of the methods discussed above--McKennis, Sanders, and Haglid--derive optically active nicotine analogs from natural (S)-(-)-nicotine. This not only limits the flexibility of pyridine substitution (Haglid was able to produce only mixtures of 4-, 6-, and possibly 2-methylnicotine), but also restricts the scope of possible products to (S)-nicotinoids.
No direct synthesis of enantiomerically pure nicotine or nicotine analogs containing alkyl substituents on the pyridine ring exist in the literature. (In this context, the term "direct" connotes a synthesis from commercially available enantiomers wherein an enantiomerically pure product is recovered without the need for resolving a racemic or partially racemic mixture.) Because indirect synthesis of enantiomerically pure nicotine analogs are difficult and time consuming, generally requiring formation and separation (e.g., fractional crystallization) of diastereomeric salts, direct synthetic methods from commercially available compounds are highly desirable.
A preferred embodiment of the process of this invention employs commercially-available enantiomers of prolinol and the precursor enantiomers of proline as starting materials for the preparation of corresponding optically active N-substituted 2-hydroxymethylpyrrolidines. The hydroxymethyl enantiomer is converted to an optically active N-substituted 2-cyanomethylpyrrolidine via an N-substituted 2-chloromethylpyrrolidine, a pyridine-ring-forming group is added to the cyanomethylpyrrolidine, and the optically active nicotine or nicotine analog is formed by ring closure of the resulting compound and subsequent reduction.
The compound 1-methyl-2-hydroxymethylpyrrolidine (i.e., 1-methylprolinol) has been produced from a variety of starting materials, but those known starting materials do not include prolinol or optically active prolinol. U.S. Pat. No. 2,695,301 discloses a method comprising the reduction of a pyrrolidine obtained from diethyl glutamate with lithium aluminum hydride following by reaction with chloral and reduction of the N-formyl derivative thus formed with lithium aluminum hydride. Also see Blicke, F. F., and Lu, C., J. Am. Chem. Soc., 77, 29 (1955). Renshaw suggests a preparation from ethyl 1-methylpyrrole-2-carboxylate by reduction with sodium and ethanol. Renshaw and Cass, J. Am. Chem. Soc., 61, 1195 (1939). Both of the foregoing methods have been criticized because they require expensive starting materials or reagents for the preparation of the required product. British Pat. No. 820,503 at p. 1, lines 14-29. Soulal prepared separable mixtures of 1-alkyl-2-hydroxymethylpyrrolidines and isomeric 3-hydroxypiperidines by producing 2,5-dibromoamyl acetate from tetrahydrofurfuryl alcohol by ring opening with HBr in an alkyl carboxylic acid (e.g., acetic acid) and ring closing of the dihalogeno-amyl acetate with a primary amine followed by saponification. Id. Alkaline hydrolysis of 1-methyl-3-chloropiperidine has been found to yield 1-methyl-2-hydroxymethylpyrrolidine as the only product. Brain, E. G., Doyle, F. P., and Mehta, M. D., J. Chem. Soc. 633 (1961). Of the foregoing methods, only that of Blicke (U.S. Pat. No. 2,695,301) may produce an optically active product [see Brain, supra, at 634, second full paragraph.]
Quantitative conversion of racemic 1-methyl-2-hydroxymethylpyrrolidine to racemic 1-methyl-2-chloromethylpyrrolidine hydrochloride with an excess of thionyl chloride in chloroform is well known in the literature. Id. at 636; Ikegami, S., Uoji, K., and Akaboshi, S., Tetrahedron, 30, 2077, 2082 (1974). Similarly, replacement reactions of a racemic chloromethyl compound with a nucleophilic cyanide reagent are suggested by the literature. Bull, Soc. Chim. France 1958, 736, 741 (refluxed 1-ethyl-3-chloropiperidine with KCN to form 1-ethyl-2-cyanomethylpyrrolidine); Brain supra at p. 639 (refluxed 1-methyl-3-chloropiperidine with NaCN to form 1-methyl-2-cyanomethylpyrrolidine). However, note that the replacement reactions suggested involved 1-alkyl-3-chloropiperidine and that only the corresponding 1-alkyl-2-cyanomethylpyrrolidine derivatives rather than mixtures of pyrrolidine and piperidine products resulted. Furthermore, direct displacement of a 1-alkyl-2-chloromethyl pyrrolidine has not been shown in the literature.
Regarding the ring closure of the cyanomethylpyrrolidine contemplated by the present inventors, methyl 2-bromonicotinate has been prepared from methyl 2-cyano-5-methoxy-2,4-pentadienoate with 30% HBr/acetic acid. Bryson, T. A., et al., J. Org. Chem., 39, 3436 (1974). However, Bryson states that an ester moiety is important to the cyclization. Id. at 3437. Cyclization of the cyanomethylpyrrolidine derivative produced according to the process of the present invention has been successfully effected without the presence of an ester functionality.